An investigation will be made of a previously undescribed property of snake venoms: namely, the enzymatic inactivation of human plasma proteinase inhibitors (PPI). This property of venom represents a means for altering the snakebite victins' regulatory control over endogenous proteolytic activity. Preliminary experiments indicate that proteinases from C. adamanteus venom enzymatically inactivate human alpha proteinase inhibitor (alpha 1 PI) by limited proteolysis. Incubation with venom also results in the loss from human plasma of all detectable trypsin and chymotrypsin inhibitory activity. The inhibitors alpha macroglobulin (alpha M), alpha 1 antichymotrypsin alpha 1 X), inter alpha trypsin inhibitor (I alpha I) and antithrombin III (ATIII) are also inactivated by venom proteases. The research will initially involve purification of the venom proteinase(s) and a study of the mechanism of inactivation of alpha 1 PI. The composition of the inactivation products will be determined and the site of the inactivating cleavage located. Purification of venom proteinases inactivating alpha 2M, alpha 1 X, ATIII, and I alpha I will then be carried out. The mechanism of inactivation of these plasma protease inhibitors will be studied. The objective of the proposed investigation is to further knowledge of the mechanism of interaction between PPI and proteolytic enzymes. A better understanding of the role of proteolysis in snakebite pathogenesis and venom toxicology should result. The inactivating proteinases could prove useful in studying the role of PPI in the biological control of physiological processes. The proteinases may also be applicable to animal model systems for in vivo studies of human diseases (e.g., emphysema) which are known to involve deficiencies of specific PPI.